US11319322B2 - Substituted aryl ether compound, preparation method thereof, pharmaceutical composition and use thereof - Google Patents

Substituted aryl ether compound, preparation method thereof, pharmaceutical composition and use thereof Download PDF

Info

Publication number
US11319322B2
US11319322B2 US16/626,015 US201816626015A US11319322B2 US 11319322 B2 US11319322 B2 US 11319322B2 US 201816626015 A US201816626015 A US 201816626015A US 11319322 B2 US11319322 B2 US 11319322B2
Authority
US
United States
Prior art keywords
alkyl
optionally substituted
esi
nmr
mhz
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
US16/626,015
Other languages
English (en)
Other versions
US20200123162A1 (en
Inventor
Xianming Deng
Ting Zhang
Qiaofeng Kang
Yanru Yang
Xihuan SUN
Zaiyou Yang
Xiaoyang Li
Jingfang Zhang
Jiaji Zhong
Zhou Deng
Chao Dong
Shuang Liu
Li Li
Qingyan XU
Zhiyu Hu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Xiamen University
Original Assignee
Xiamen University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Xiamen University filed Critical Xiamen University
Assigned to XIAMEN UNIVERSITY reassignment XIAMEN UNIVERSITY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DENG, XIANMING, DENG, Zhou, DONG, CHAO, HU, ZHIYU, KANG, Qiaofeng, LI, LI, LI, XIAOYANG, LIU, SHUANG, SUN, Xihuan, XU, Qingyan, YANG, Yanru, YANG, Zaiyou, ZHANG, Jingfang, ZHANG, TING, ZHONG, Jiaji
Publication of US20200123162A1 publication Critical patent/US20200123162A1/en
Application granted granted Critical
Publication of US11319322B2 publication Critical patent/US11319322B2/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/28—Oxygen atom
    • C07D473/30—Oxygen atom attached in position 6, e.g. hypoxanthine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the invention relates to the field of medicinal chemistry, and in particular to a type of compounds having RET kinase selective inhibitory activity, a method for the preparation thereof, a pharmaceutical composition comprising the same, and use of these compounds in the manufacture of a medicament for preventing or treating a disease associated with RET kinase in vivo, and in the manufacture of a medicament for preventing or treating a disease associated with angiogenesis or cancer metastasis, in particular in the manufacture of a medicament for preventing or treating tumor growth and metastasis.
  • Lung cancer is the first killer to threat human health today.
  • the use of targeted drugs for the treatment of lung cancer has made a great progress.
  • a series of small molecule drugs targeting kinases such as Imatinib, Gefitinib, Ceritinib and Sunitinib, have been successfully used in clinical practice. Also, there are more kinase inhibitors in development or in clinical trials.
  • RET kinase is a receptor tyrosine kinase expressed by RET proto-oncogene.
  • the protein structure includes, in the order from N-terminus to C-terminus, an extracellular receptor domain, a transmembrane domain, and an intracellular tyrosine kinase domain.
  • the protein consists of 1114 amino acids, of which 724 to 1016 are kinase domains.
  • RET kinase protein fused to other proteins can be used as a potential therapeutic target.
  • proteins that can be fused to RET kinase are kinesin family member 5B (KIF5B), coiled-coli domain containing 6 (CCDC6), tripartite motif-containing 33 (TRIM33), and nuclear receptor coactivator 4 (NOCA4).
  • KIF5B-RET fusion protein accounts for 90% of all RET fusion proteins.
  • RET fusion proteins are independent of other cancer driver factors such as EGFR, HER2, BRAF or ELM4-ALK.
  • the compound has the general formula:
  • One object of the present invention is to provide a compound having RET selective inhibitory activity, and a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof.
  • Another object of the present invention is to provide a method for the preparation of the above compound.
  • Another object of the present invention is to provide a pharmaceutical composition comprising the above compound.
  • Another object of the present invention is to provide use of the above compound in the manufacture of a medicament for preventing or treating a disease associated with RET kinase accompanied by abnormal cell proliferation, morphological changes, hyperkinesia and the like in vivo, and in the manufacture of a medicament for preventing or treating a disease associated with angiogenesis or cancer metastasis, in particular in the manufacture of a medicament for preventing or treating tumor growth and metastasis.
  • the present invention is achieved by the following technical solutions.
  • the present invention provides a compound having the general formula, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof,
  • R 1 is selected from:
  • aryl or heteroaryl is optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C3 fluorine-containing alkyl; C3-C6 cycloalkyl, halogen; nitro, cyano, hydroxy, optionally substituted heterocyclyl, C1-C6 alkoxycarbonyl, C1-C6 acyl;
  • a five- or six-membered heterocyclic ring comprising one or more heteroatoms selected from N, O and S, said five- or six-membered heterocyclic ring being optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, hydroxy; amino; C1-C6 alkoxycarbonyl, C1-C6 acyl, cyano, optionally substituted heterocyclyl, including but not limited to: morpholine, 3,5-dimethylmorpholino, thiomorpholinyl, tetrahydropyrrolyl, 3-N,N-dimethyltetrahydropyrrolyl, 3-N,N-diethyltetrahydropyrrolyl;
  • piperidinyl 4-N,N-dimethylaminopiperidinyl, 4-N,N-diethylaminopiperidinyl, 4-N,N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-(N-methylpiperazinyl)piperidinyl, 4-(N-ethylpiperazinyl)piperidinyl, 4-(N-isopropylpiperazinyl)piperidinyl, 4-(N-acetylpiperazinyl)piperidinyl; 4-(N-t-butoxyformylpiperazinyl)piperidinyl, 4-(N-methanesulfonylpiperazinyl)piperidinyl, 4-(N-(2-hydroxyethyl)piperazinyl)piperidinyl, 4-(N-(2-cyanoethyl)piperazinyl)piperidinyl, 4-(N-(3-hydroxypropyl)piperazin
  • R 1 is selected from:
  • aryl or heteroaryl is optionally substituted by C1-C6 alkyl, 01-C6 alkoxy, C1-C3 fluorine-containing alkyl, C3-C6 cycloalkyl, halogen, amino; hydroxy, optionally substituted heterocyclyl;
  • R 2 is selected from: hydrogen, halogen atom, optionally substituted 01-C6 alkyl, optionally substituted C3-C7 cycloalkyl, C1-C6 fluorine-containing alkyl, optionally substituted C6-C10 aryl or optionally substituted heteroaryl;
  • R 3 is selected from optionally substituted 06-010 aryl or optionally substituted heteroaryl, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, optionally substituted heterocyclyl, the substituent thereof being selected from: optionally substituted heterocyclyl, hydroxy, C1-C6 fluorine-containing alkyl, optionally substituted C6-C10 aryl, optionally substituted heteroaryl;
  • the pharmaceutically acceptable salt is preferably an inorganic acid salt or an organic acid salt, wherein the inorganic acid salt is selected from hydrochloride, hydrobromide, nitrate, sulfate or phosphate; the organic acid salt is selected from formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, alkyl sulfonate or aryl sulfonate; preferably, said alkyl sulfonate is methyl sulfonate or ethyl sulfonate; said aryl sulfonate is benzenesulfonate or p-toluenesulfonate.
  • the inorganic acid salt is selected from hydrochloride, hydrobromide, nitrate, sulfate or phosphate
  • the organic acid salt is selected from formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tart
  • the present invention is further achieved by the following technical solution; wherein as for the compound, or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, the compound has the following general formulas I-VII:
  • the compound has the following structure:
  • R 1 is selected from: hydrogen, optionally substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, optionally substituted C3-C7 cycloalkyl, nitro, cyano, amino, hydroxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, the substituent thereof being selected from: halogen atom, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, nitro, cyano,
  • R 1 is selected from: hydrogen, optionally substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl, optionally substituted C3-C7 cycloalkyl, hydroxy, amino, optionally substituted C6-C10 aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, the substituent thereof being selected from: halogen atom, amino, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl;
  • R 1 is selected from: hydrogen, C1-C6 alkoxy, optionally substituted C3-C7 cycloalkyl, hydroxy, amino, optionally substituted C6-C10 aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, the substituent thereof being selected from: fluoro, chloro, bromo, amino, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl;
  • R 1 is selected from:
  • R 2 is selected from: hydrogen, halogen atom, C1-C6 alkyl, C1-C6 fluorine-containing alkyl;
  • R 2 is selected from: hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, trifluoromethyl;
  • R 2 is selected from: H, 4-Cl, 4-CH 3 , 6-CH 3 ;
  • R 3 is selected from optionally substituted C6-C10 aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, the substituent thereof being selected from: halogen atom, optionally substituted C6-C10 aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, nitro, cyano, amino, hydroxy;
  • R 3 is selected from: mono- or di-substituted or unsubstituted C6-C10 aryl or heteroaryl, the substituent thereof being: optionally substituted C1-C6 alkyl, the substituent on the C1-C6 alkyl being heterocyclyl substituted by C1-C6 alkyl; C1-C6 fluorine-containing alkyl, heterocyclyl substituted by C1-C6 alkyl;
  • R 3 is
  • Z 1 -Z 5 is CF 3 —, the rest being H; or any two of Z 2 , Z 3 , Z 4 each are independently selected from CF 3 —,
  • R 3 is
  • Z 4 is CF 3 —, the rest being H; or Z 4 is CF 3 —, one of Z 2 , Z 3 is
  • R 4 is selected from: hydrogen, C1-C6 alkyl, C1-C6 fluorine-containing alkyl, tri(C1-C6 alkyl) silyl C1-C6 alkoxy C1-C6 alkyl;
  • R 4 is selected from: hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, tri(C1-C6 alkyl) silyl C1-C6 alkoxy C1-C6 alkyl;
  • R 4 is selected from hydrogen, methyl, isopropyl, trimethylsilylethoxymethyl (-SEM);
  • the compound has the following structure:
  • R 1 is selected from:
  • arylamino or heteroarylamino wherein the aryl or heteroaryl is optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C3 fluorine-containing alkyl, C3-C6 cycloalkyl, halogen, nitro, cyano, hydroxy, optionally substituted heterocyclyl, C1-C6 alkoxycarbonyl, C1-C6 acyl;
  • R 1 is selected from:
  • arylamino or heteroarylamino wherein the aryl or heteroaryl is optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, C1-C3 fluorine-containing alkyl, C3-C6 cycloalkyl, halogen, amino, hydroxy, optionally substituted heterocyclyl;
  • R 1 is selected from:
  • arylamino or heteroarylamino wherein the aryl or heteroaryl is optionally substituted by methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoro, chloro, bromo, hydroxy, optionally substituted heterocyclyl;
  • R 1 is selected from: —H,
  • R 2 is selected from: hydrogen, halogen atom, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, the substituent thereof being selected from halogen atom;
  • R 2 is selected from: hydrogen, halogen atom, C 1-6 alkyl, C1-C6 fluorine-containing alkyl;
  • R 2 is selected from: hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, trifluoromethyl;
  • R 2 is selected from: H, 4-Cl, 4-CH 3 , 6-CH 3 ;
  • R 3 is selected from optionally substituted C6-C10 aryl or optionally substituted heteroaryl, optionally substituted C1-C6 alkyl, the substituent thereof being selected from: optionally substituted C1-C6 alkyl, optionally substituted heterocyclyl, hydroxy, C1-C6 fluorine-containing alkyl, optionally substituted C6-C10 aryl, optionally substituted heteroaryl;
  • R 3 is selected from: optionally substituted or unsubstituted C1-C6 alkyl, the substituent thereof being selected from: optionally substituted heterocyclyl, hydroxy; mono- or di-substituted or unsubstituted C6-C10 aryl, the substituent thereof being selected from: optionally substituted C1-C6 alkyl, the substituent on the C1-C6 alkyl being heterocyclyl substituted by C1-C6 alkyl; C1-C6 fluorine-containing alkyl, heterocyclyl substituted by one of C1-C6 amido, C1-C6 amido C1-C6 alkyl or C1-C6 alkyl, heteroaryl substituted by C1-C6 alkyl;
  • R 3 is selected from: 1)
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are all H: or Z 4 is CF 3 —, the rest being H: or Z 4 is CF 3 —, one of Z 2 , Z 3 is selected from CF 3 —,
  • R 5 is selected from: hydrogen, C 1-6 alkyl, C1-C6 fluorine-containing alkyl;
  • R 5 is selected from: hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl;
  • R 5 is hydrogen, methyl, ethyl, isopropyl
  • the compound has the following structure:
  • R 1 is selected from:
  • arylamino or heteroarylamino wherein the aryl or heteroaryl is optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C3 fluorine-containing alkyl, C3-C6 cycloalkyl, halogen, nitro, cyano, hydroxy, optionally substituted heterocyclyl, C1-C6 alkoxycarbonyl, C1-C6 acyl;
  • R 1 is selected from:
  • arylamino or heteroarylamino wherein the aryl or heteroaryl is optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, C1-C3 fluorine-containing alkyl, C3-C6 cycloalkyl, halogen, hydroxy, optionally substituted heterocyclyl;
  • R 1 is selected from:
  • R 1 is selected from: —H, —OH,
  • R 2 is selected from: hydrogen, halogen atom, optionally substituted C1-C6 alkyl, C1-C6 fluorine-containing alkyl, optionally substituted C6-C10 aryl or optionally substituted heteroaryl;
  • R 2 is selected from: hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, trifluoromethyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, thiazolyl, isothiazolyl, thioxazolyl, pyrrolyl, furyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, indazolyl, quinolyl, isoquinolyl;
  • R 2 is selected from: H,
  • R 3 is selected from mono- or di-substituted or unsubstituted C6-C10 aryl or heteroaryl, the substituent thereof being: optionally substituted C1-C6 alkyl, the substituent on the C1-C6 alkyl being heterocyclyl substituted by C1-C6 alkyl; C1-C6 fluorine-containing alkyl, heterocyclyl substituted by one of C1-C6 amido, C1-C6 amido C1-C6 alkyl or C1-C6 alkyl, heteroaryl substituted by C1-C6 alkyl;
  • R 3 is
  • Z 1 -Z 5 is CF 3 —, the rest being H; or any two of Z 2 , Z 3 , Z 4 each are independently selected from CF 3 —,
  • R 3 is
  • Z 4 is CF 3 —, the rest being H; or Z 4 is CF 3 —, one of Z 2 , Z 3 is
  • R 6 is selected from: hydrogen, C 1-6 alkyl, C1-C6 fluorine-containing alkyl;
  • R 6 is selected from: hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl;
  • R 6 most preferably, is hydrogen, methyl
  • L is selected from: —NHCO—, —CONH—, —NHSO 2 —, —SO 2 NH—, —NHCONH—, —NHCSNH—, —COO—, —OCO—; L, preferably, is selected from: —NHCO—, —CONH—.
  • the compound has the following structure:
  • R 1 is selected from: hydrogen, optionally substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, optionally substituted C3-C7 cycloalkyl, nitro, cyano, amino, hydroxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, the substituent thereof being selected from halogen atom, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, nitro, cyano, amino
  • R 1 is selected from: hydrogen, optionally substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl, optionally substituted C3-C7 cycloalkyl, hydroxy, amino, optionally substituted C6-C10 aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, the substituent thereof being selected from halogen atom, amino, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl;
  • R 1 is selected from: hydrogen, C1-C6 alkoxy, optionally substituted C3-C7 cycloalkyl, hydroxy, amino, optionally substituted C6-C10 aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, the substituent thereof being selected from fluoro, chloro, bromo, amino, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl;
  • R 1 is selected from: —H,
  • R 2 is selected from: hydrogen, halogen atom, C 1-6 alkyl, C1-C6 fluorine-containing alkyl;
  • R 2 is selected from: hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, trifluoromethyl;
  • R 2 is selected from: H, 4-Cl, 4-CH 3 , 6-CH 3 ;
  • R 3 is selected from mono- or di-substituted or unsubstituted C6-C10 aryl or heteroaryl, the substituent thereof being: optionally substituted C1-C6 alkyl, the substituent on the C1-C6 alkyl being heterocyclyl substituted by C1-C6 alkyl; C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, heterocyclyl substituted by C1-C6 alkyl, heteroaryl substituted by C1-C6 alkyl;
  • R 3 is
  • Z 1 -Z 5 is CF 3 — or CF 3 O—, the rest being H; or any two of Z 2 , Z 3 , Z 4 each are independently selected from CF 3 —,
  • R 3 most preferably, is
  • Z 4 is CF 3 — or CF 3 O—, the rest being H; or Z 4 is CF 3 —, one of Z 2 , Z 3 is
  • R 7 is selected from: C1-C6 alkyl, C1-C6 fluorine-containing alkyl;
  • R 7 is selected from: methyl, ethyl, propyl, isopropyl, trifluoromethyl;
  • R 7 is selected from methyl
  • L is selected from: —NHCO—, —CONH—, —NHSO 2 —, —SO 2 NH—, —NHCONH—, —NHCSNH—, —COO—, —OCO—; L, preferably, is selected from: —NHCO—, —CONH—.
  • the compound has the following structure:
  • R 1 is selected from: hydrogen, C1-C6 amido, optionally substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, optionally substituted C3-C7 cycloalkyl, nitro, cyano, amino, hydroxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, the substituent thereof being selected from halogen atom, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl,
  • R 1 is selected from: hydrogen, C1-C6 amido, optionally substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, optionally substituted C3-C7 cycloalkyl, hydroxy, amino, optionally substituted C6-C10 aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, the substituent thereof being selected from halogen atom, amino, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl;
  • R 1 is selected from: hydrogen, C1-C6 amido, C1-C6 alkoxy, optionally substituted C3-C7 cycloalkyl, hydroxy, amino, optionally substituted C6-C10 aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, the substituent thereof being selected from fluoro, chloro, bromo, amino, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl; most preferably, R 1 is selected from:
  • R 2 is selected from: hydrogen, halogen atom, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, the substituent thereof being selected from halogen atom;
  • R 2 is selected from: hydrogen, halogen atom, C 1-6 alkyl, C1-C6 fluorine-containing alkyl;
  • R 2 is selected from: hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, trifluoromethyl;
  • R 2 is selected from: H, 4-CH 3 , 6-CH 3 ;
  • R 3 is selected from: optionally substituted C6-C10 aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, the substituent thereof being selected from: halogen atom, optionally substituted C6-C10 aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, nitro, cyano, amino, hydroxy;
  • R 3 is selected from: mono- or di-substituted or unsubstituted C6-C10 aryl or heteroaryl, the substituent thereof being: optionally substituted C1-C6 alkyl, the substituent on the C1-C6 alkyl being heterocyclyl substituted by C1-C6 alkyl; C1-C6 fluorine-containing alkyl, heterocyclyl substituted by C1-C6 alkyl;
  • R 3 is
  • Z 1 -Z 5 is CF 3 —, the rest being H; or any two of Z 2 , Z 3 , Z 4 each are independently selected from CF 3 —,
  • R 3 most preferably, is
  • Z 4 is CF 3 —, the rest being H; or Z 4 is CF 3 —, one of Z 2 , Z 3 is
  • R 8 is selected from: hydrogen, C1-C6 alkyl, C1-C6 fluorine-containing alkyl;
  • R 8 is selected from: hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl;
  • R 8 is selected from hydrogen, methyl
  • the compound f has the following structure:
  • R 1 is selected from: hydrogen, C1-C6 amido, optionally substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, optionally substituted C3-C7 cycloalkyl, nitro, cyano, amino, hydroxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, the substituent thereof being selected from halogen atom, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl,
  • R 1 is selected from: hydrogen, C1-C6 amido, optionally substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, optionally substituted C3-C7 cycloalkyl, hydroxy, amino, optionally substituted C6-C10 aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, the substituent thereof being selected from halogen atom, amino, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl;
  • R 1 is selected from: hydrogen, C1-C6 alkoxy, optionally substituted C3-C7 cycloalkyl, hydroxy, amino, optionally substituted C6-C10 aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, the substituent thereof being selected from fluoro, chloro, bromo, amino, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl;
  • R 1 is selected from:
  • R 2 is selected from: hydrogen, halogen atom, C 1-6 alkyl, C1-C6 fluorine-containing alkyl;
  • R 2 is selected from: hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, trifluoromethyl;
  • R 2 is selected from: H, 4-Cl, 4-CH 3 , 6-CH 3 ;
  • R 3 is selected from: optionally substituted C6-C10 aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, the substituent thereof being selected from halogen atom, optionally substituted C6-C10 aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, nitro, cyano, amino, hydroxy;
  • R 3 is selected from: mono- or di-substituted or unsubstituted C6-C10 aryl or heteroaryl, the substituent thereof being: optionally substituted C1-C6 alkyl, the substituent on the C1-C6 alkyl being heterocyclyl substituted by C1-C6 alkyl; C1-C6 fluorine-containing alkyl, heterocycyl substituted by C1-C6 alkyl;
  • R 3 is
  • any two of Z 2 , Z 3 , Z 4 each are independently selected from CF 3 —,
  • R 3 most preferably, is
  • Z 4 is CF 3 —, one of Z 2 , Z 3 is
  • the compound has the following structure:
  • R 1 is selected from: hydrogen, C1-C6 amido, optionally substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, optionally substituted C3-C7 cycloalkyl, nitro, cyano, amino, hydroxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, the substituent thereof being selected from halogen atom, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl,
  • R 1 is selected from: hydrogen, C1-C6 amido, optionally substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, optionally substituted C3-C7 cycloalkyl, hydroxy, amino, optionally substituted C6-C10 aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, the substituent thereof being selected from fluoro, chloro, bromo, amino, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl;
  • R 1 is selected from: hydrogen, C1-C6 alkoxy, optionally substituted C3-C7 cycloalkyl, hydroxy, amino, optionally substituted C6-C10 aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, the substituent thereof being selected from fluoro, chloro, bromo, amino, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl;
  • R 1 is selected from:
  • R 2 is selected from: hydrogen, halogen atom, C1-C6 alkyl, C1-C6 fluorine-containing alkyl;
  • R 2 is selected from: hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, trifluoromethyl;
  • R 2 is selected from: H, 4-Cl, 4-CH 3 , 6-CH 3 ;
  • R 3 is selected from: optionally substituted C6-C10 aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted C1-C6 alkyl, optionally substituted C3-C7 cycloalkyl, the substituent thereof being selected from halogen atom, optionally substituted C6-C10 aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, nitro, cyano, amino, hydroxy;
  • R 3 is selected from: mono- or di-substituted or unsubstituted C6-C10 aryl or heteroaryl, the substituent thereof being: optionally substituted C1-C6 alkyl, the substituent on the C1-C6 alkyl being heterocyclyl substituted by C1-C6 alkyl; C1-C6 fluorine-containing alkyl; heterocyclyl substituted by C1-C6 alkyl; heteroaryl substituted by C1-C6 alkyl;
  • R 3 is
  • any two of Z 2 , Z 3 , Z 4 each are independently selected from CF 3 —,
  • R 3 most preferably, is
  • Z 4 is CF 3 —, one of Z 2 , Z 3 is
  • the present invention is further achieved by the following technical solution, wherein the compounds of formulas I-VII form, with a certain amount (e.g., equal amount of substance) of an acid, a pharmaceutically acceptable salt, wherein the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt, wherein the inorganic acid salt is selected from hydrochloride, hydrobromide, nitrate, sulfate or phosphate; the organic acid salt is selected from formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, alkyl sulfonate or aryl sulfonate; preferably, said alkyl sulfonate is methyl sulfonate or ethyl sulfonate; said aryl sulfonate is benzenesulfonate or p-toluenesulfonate.
  • the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid
  • the present invention is further achieved by the following technical solution wherein the compounds of formulas I-VII are formed into a pharmaceutical composition, comprising a pharmaceutically acceptable solvate and a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention is further achieved by the following technical solution, which provides a preparation method of the compounds of formulas I-VII and salts thereof, comprising the following steps:
  • R 1 , R 2 , R 3 , A, X, L are as defined above; R refers to a reactive group, selected from hydrogen, boric acid group or borate ester group and the like.
  • the present invention is further achieved by the following technical solution, which provides a preparation method of the compounds of formulas I-VII and salts thereof, characterized in the following aspects.
  • the base used is selected from an organic base (such as n-butyl lithium, sodium methoxide, sodium ethoxide, potassium t-butoxide and the like) or an inorganic base (such as sodium carbonate, potassium carbonate, cesium carbonate and the like), preferably sodium carbonate or potassium carbonate.
  • an organic base such as n-butyl lithium, sodium methoxide, sodium ethoxide, potassium t-butoxide and the like
  • an inorganic base such as sodium carbonate, potassium carbonate, cesium carbonate and the like
  • the metal catalyst used is a zero-valent transition metal catalyst (such as Pd(dppf)Cl 2 .CH 2 Cl 2 , Pd(OAc) 2 , Pd(PPh 3 ) 4 , Ni(cod 2 ), Ni(dppf)Cl 2 and the like), preferably Pd(dppf)Cl 2 .CH 2 Cl 2 ;
  • the solvent used is, but not limited to, toluene, tetrahydrofuran, N,N-dimethylformamide, water or a mixed solvent, preferably tetrahydrofuran/water mixed solvent;
  • the base used is, but not limited to, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, barium hydroxide, potassium fluoride, cesium fluoride, sodium tert-butoxide, preferably sodium carbonate or potassium carbonate.
  • the metal catalyst used is a zero-valent transition metal catalyst (such as Pd 2 (dba) 3 , Pd(OAc) 2 , Pd(dppf)Cl 2 .CH 2 Cl 2 and the like), preferably Pd 2 (dba) 3 ;
  • the phosphorus ligand used is but not limited to;
  • the solvent used is, but not limited to, toluene, tetrahydrofuran, N,N-dimethylformamide, tert-butanol, preferably tert-butanol;
  • the base used is, but not limited to, potassium carbonate, cesium carbonate, sodium tert-butoxide, lithium hexamethyldisilazide (LHMDS), preferably potassium carbonate or cesium carbonate.
  • the base used is selected from an organic base (such as triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine and the like) or an inorganic base (such as sodium carbonate, potassium carbonate, cesium carbonate and the like), preferably triethylamine or diisopropylethylamine;
  • the solvent used is, but not limited to, toluene, tetrahydrofuran, N,N-dimethylformamide, tert-butanol, preferably tetrahydrofuran.
  • C1-C6 alkyl refers to any straight-chain or branched-chain group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, tert-amyl, n-hexyl and the like.
  • C2-C6 alkenyl refers to any straight-chain or branched-chain group containing 2 to 6 carbon atoms and containing at least one alkenyl, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 1-hexenyl and the like.
  • C2-C6 alkynyl refers to any straight-chain or branched-chain group containing 2 to 6 carbon atoms and containing at least one alkynyl, such as ethynyl, 2-propynyl, 4-pentynyl and the like.
  • C1-C6 amido refers to any straight-chain or branched-chain group containing amido (CONH 2 ), having 1 to 6 carbon atoms and, such as formamide, acetamido, propionamide, butanamide, valeramide, caproamide and the like.
  • C3-C7 cycloalkyl refers to a 3- to 7-membered all-carbon monocyclic ring that may contain one or more double bonds, but does not have a fully conjugated ⁇ -electron system.
  • Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl.
  • sil refers to a silyl group, r1r2r3r4-Si, that is, SiH 4 wherein H atom(s) is (are) substituted by 1 to 4 organic groups mentioned in the present invention, such as “C1-C6 alkyl”, “C1-C3 alkyl”, “C2-C6 alkenyl”, “C2-C6 alkynyl”, “C3-C7 cycloalkyl”, “C1-C6 amido”, “C1-C6 amido C1-C6 alkyl”, “halogen atom”, hydroxy, amino, nitro, cyano and the like.
  • fluorine-containing alkyl or “polyfluorinated alkyl” refers to a group in which alkyl skeleton is substituted by one or more fluoro groups, for example, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl and the like.
  • C1-C6 acyl refers to —C( ⁇ O)—H and —C( ⁇ O)—C1-C5 alkyl, such as formyl, acetyl, propionyl, butanoyl and the like.
  • C1-C6 oxygen-containing alkyl refers to a group in which C1-C6 alkyl skeleton is substituted by one or more C1-C6 alkoxy groups, for example, methoxyethyl, methoxyethoxymethyl and the like.
  • halogen refers to a fluoro (F), chloro (Cl), bromo (Br) or iodine (I) atom.
  • cyano refers to —CN residue.
  • nitro refers to —NO 2 group.
  • aryl or C6-C10 aryl refers to a C6-C10 mono-, di- or poly-carbocyclic hydrocarbon having from 1 to 2 ring systems which are optionally further fused or attached to each other by a single bond, wherein at least one of the carbon rings is “aromatic”, and the term “aromatic” refers to a fully conjugated ⁇ -electron bond system.
  • the aryl ring may be optionally further fused or attached to aromatic or non-aromatic carbocyclic rings or heterocyclic rings.
  • Non-limiting examples of the aryl group are phenyl, ⁇ - or ⁇ -naphthyl.
  • heteroaryl refers to an aromatic heterocyclic ring, which is usually a 5- to 8-membered heterocyclic ring having from 1 to 3 heteroatoms selected from N, O or S; a heteroaryl ring may be optionally further fused or attached to aromatic or non-aromatic carbocyclic rings or heterocyclic rings.
  • Non-limiting examples of the heteroaryl group are, for example, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, isothiazolyl, thioxazolyl, pyrrolyl, phenyl-pyrrolyl, furyl, phenyl-furyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzothienyl, isoindolinyl, benzoimidazolyl, indazolyl, quinolyl, isoquinolyl, 1,2,3-triazolyl, 1-phenyl-1,2,3-triazolyl, 2,3-indolinyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, benzopyranyl, 2,3-dihydrobenzoxazinyl, 2,3-
  • heterocyclyl (also referred to as “heterocycloalkyl”) refers to 3-, 4-, 5-, 6- and 7-membered saturated or partially unsaturated carbocyclic rings, wherein one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur.
  • Non-limiting examples of the heterocyclic group are, for example, pyranyl, pyrrolidinyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, thiazolinyl, thiazolidinyl, dihydrofuryl, tetrahydrofuryl, 1,3-dioxolanyl, piperidinyl, piperazinyl, morpholine, morpholinyl, tetrahydropyrrolyl, thiomorpholinyl and the like.
  • heterocyclyl refers to that the above-mentioned “heterocyclyl” is substituted by one or more “C1-C6 alkyl”, “C1-C3 alkyl”, “C3-C6 cycloalkyl”, “C1-C6 amido”, “C1-C6 amido C1-C6 alkyl”, “halogen atom”, hydroxy, amino, nitro, cyano and the like, or not substituted.
  • optionally substituted XX group refers to that the “XX group” is substituted by one or more “C1-C6 alkyl”, “optionally substituted C1-C6 alkyl”, “C1-C3 alkyl”, “C3-C6 cycloalkyl”, “C1-C6 amido”, “C1-C6 amido C1-C6 alkyl”, “heterocyclyl”, “halogen atom”, hydroxy, amino, nitro, cyano and the like, or unsubstituted.
  • any of the above groups being “optionally substituted” also refers to that it may optionally be substituted at any of its free positions by one or more groups, for example by 1 to 6 groups, the groups being independently selected from: halogen atom, nitro, oxo ( ⁇ O), cyano, C1-C6 alkyl, polyfluorinated alkyl, polyfluorinated alkoxy, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkylamino, hydroxyheterocyclyl, aryl, aryl-alkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl, heterocyclyl-alkyl, C3-C7 cycloalkyl, cycloalkyl-alkyl, alkyl-aryl, alkyl-heteroaryl, alkyl-heterocyclyl, alkyl-cycloalkyl, alkyl-aryl-alkyl, alkyl-aryl-alkyl,
  • each of the above substituents may be further substituted by one or more of the above-exemplified groups.
  • alkoxy refers to any of the above C1-C6 alkyl, C3-C7 cycloalkyl, aryl or heterocyclyl, which is attached to the remainder of molecules through oxygen atom (—O—).
  • arylamino shall mean that it is conventionally constructed from the moiety that is derived, such as the amino substituted by the aryl, wherein the aryl is as defined above.
  • any term such as alkylthio, alkylamino, heteroarylamino, dialkylamino, fluorine-containing alkoxy, polyfluorinated alkyl, polyfluorinated alkoxy, alkoxycarbonyl, alkoxycarbonylamino, heterocyclylcarbonyl, heterocyclylcarbonylamino, cycloalkyloxycarbonyl and the like includes groups, wherein alkyl, alkoxy, aryl, C3-C7 cycloalkyl and heterocyclyl moieties are as defined above.
  • prodrug refers to a derivative that can be hydrolyzed, oxidized or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound of the invention.
  • Prodrugs can become active compounds only by carrying out the reaction under biological conditions, or they are inactive in their non-reacted form.
  • Prodrugs can be generally prepared using known methods, for example, those methods described in 1 Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff, ed. 5 th edition).
  • compositions can be obtained using standard procedures well known in the art, for example, by reacting a sufficient amount of a basic compound with a suitable acid that provides a pharmaceutically acceptable anion.
  • treatment generally refers to obtaining the desired pharmacological and/or physiological effect.
  • the effect may be preventive according to complete or partial prevention of disease or its symptoms; and/or may be therapeutic according to partial or complete stabilization or cure of disease and/or side effects due to the disease.
  • treatment encompasses any treatment on a patient's disease, including: (a) preventing the disease or symptom that occurs in a patient who is susceptible to the disease or symptom but not yet diagnosed to suffer from the disease; (b) suppressing symptoms of the disease, i.e., stopping its development; or (c) relieving symptoms of the disease, i.e., causing degeneration of the disease or symptom.
  • the compound is one of the compounds described in the examples below.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound, a stereoisomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof or pharmaceutically acceptable solvate thereof according to any one of the above embodiments, and a pharmaceutically acceptable carrier, diluent or excipient.
  • Methods for preparing a pharmaceutical composition comprising a certain amount of an active ingredient, are known or are obvious for a person skilled in the art according to the contents as disclosed in the invention.
  • methods for preparing a pharmaceutical composition comprise incorporating a suitable pharmaceutically acceptable excipient, carrier, diluent and the like.
  • the known methods for preparing a pharmaceutical preparation according to the invention include the conventional mixing, dissolving or freeze-drying methods.
  • the compound according to the invention can be used to prepare into a pharmaceutical composition, which is administered to a patient by various routes suitable for the selected administration mode, for example, oral, or parenteral route (intravenous, intramuscular, topical, or subcutaneous route).
  • the compound of the invention in combination with a pharmaceutically acceptable carrier can be administered systemically, e.g., orally. They can be encapsulated into a hard or soft shell gelatin capsule, or pressed into a tablet.
  • a pharmaceutically acceptable carrier such as an inert diluent or an assimilable edible carrier
  • an active compound may be combined with one or more excipients, and be used in a form of a deglutible tablet, a buccal tablet, a troche, a capsule, an elixir, a suspension, a syrup, a wafer and the like.
  • the composition and preparation shall comprise at least 0.1% of an active compound.
  • the ratio of the composition to the preparation can be varied certainly, and the composition may account for about 1 wt % to about 99 wt % of a given unit dosage form.
  • the active compound is in an amount sufficient to obtain an effective dosage level.
  • a tablet, a troche, a pill, a capsule, and the like may include: a binder, such as tragacanth gum, arabic gum, maize starch or gelatin; an excipient, such as dicalcium phosphate; a disintegrant, such as maize starch, potato starch, and alginic acid etc.; a lubricant, such as magnesium stearate; and a sweeting agent, such as sucrose, fructose, lactose or aspartame; or a flavoring agent, such as peppermint, winter green oil or cherry flavor.
  • a binder such as tragacanth gum, arabic gum, maize starch or gelatin
  • an excipient such as dicalcium phosphate
  • a disintegrant such as maize starch, potato starch, and alginic acid etc.
  • a lubricant such as magnesium stearate
  • a sweeting agent such as sucrose, fructose, lactose or as
  • a tablet, a pill or a capsule may be coated with gelatin, wax, shellac or sugar etc.
  • a syrup or elixir may comprise an active compound, sucrose or fructose as a sweeting agent, methyl p-hydroxybenzoate or propyl p-hydroxybenzoate as preservative, a dye and a flavoring agent (such as a cherry flavor or an orange flavor).
  • sucrose or fructose as a sweeting agent
  • methyl p-hydroxybenzoate or propyl p-hydroxybenzoate as preservative
  • a dye and a flavoring agent such as a cherry flavor or an orange flavor.
  • any material for preparing any unit dosage form should be pharmaceutically acceptable and be substantively not toxic in its applied amount.
  • an active compound may be incorporated into a sustained release preparation and a sustained release device.
  • An active compound may also be administered intravenously or intraperitoneally by infusion or injection.
  • An aqueous solution of an active compound or a salt thereof may be prepared, optionally, by mixing it with a non-toxic surfactant.
  • a dispersible formulation in glycerol, liquid polyethylene glycol, glycerin triacetate and a mixture thereof and in oil may also be prepared. Under the common conditions of storage and use, the preparations may comprise a preservative in order to suppress the growth of microbes.
  • a pharmaceutical dosage form suitable for injection or infusion may include a sterile aqueous solution or a dispersible formulation or a sterile powder comprising an active ingredient (optionally encapsulated into a liposome) of an immediate preparation such as a solution or a dispersible formulation suitable for sterile injection or infusion.
  • the final dosage form shall be sterile, liquid and stable under the production and storage conditions.
  • a liquid carrier may be a solution or a liquid disperse medium, including, for example, water, ethanol, polyols (such as glycerol, propylene glycol, and liquid macrogol and the like), vegetable oil, a non-toxic glyceride and a suitable mixture thereof.
  • a suitable fluidity may be retained, for example, by the formation of liposome, by retaining the desired particle size in the presence of a dispersing agent, or by using a surfactant.
  • the effect of suppressing microbes can be obtained by various antibacterial agents and antifungal agents (such as paraben, chlorbutol, phenol, sorbic acid, and thiomersal and the like).
  • an isotonizing agent such as sugar, buffer agent or NaCl, is preferably comprised.
  • a composition of delayed absorbents e.g., aluminium monostearate and gelatin
  • an extended absorption of an injectable composition can be obtained.
  • a sterile injectable solution can be prepared by mixing a desired amount of an active compound in a suitable solvent with the desired various other ingredients as listed above, and then performing filtration and sterilization.
  • the preferred preparation method is vacuum drying and freeze drying techniques, which will result in the production of the powder of the active ingredient and any other desired ingredient present in the previous sterile filtration solution.
  • a useful solid carrier includes crushed solid (such as talc, clay, microcrystalline cellulose, silicon dioxide, and aluminum oxide etc.).
  • a useful liquid carrier includes water, ethanol or ethylene glycol or water-ethanol/ethylene glycol mixture, in which the compound of the invention may be dissolved or dispersed in an effective amount, optionally, with the aid of a non-toxic surfactant.
  • An adjuvant such as a flavor
  • an additional antimicrobial agent may be added to optimize the property for a given use.
  • a thickener (such as synthetic polymer, fatty acid, fatty acid salt and ester, fatty alcohol, modified cellulose or modified inorganic material) may also be used with a liquid carrier to form a coatable paste, gel, ointment, soap and the like, and be directly applied to the skin of a user.
  • a therapeutically effective amount of a compound or an active salt or derivative thereof not only depends on the specific salt selected, but also depends on the administration mode, the nature of the disease to be treated and the age and state of a patient, and finally depends on the decision made by an attending physician or a clinical physician.
  • a unit dosage form which is a physical dispersion unit comprising a unit dose, suitable for administration to a human body and other mammalian body.
  • a unit dosage form may be capsule(s) or tablet(s).
  • the amount of an active ingredient in a unit dose may be varied or adjusted between about 0.1 and about 1000 mg or more.
  • the present invention further includes use of various new drug dosage forms such as milk liposomes, microspheres and nanospheres, for example, medicaments prepared with the use of a particulate dispersion system including polymeric micelles, nanoemulsions, submicroemulsions, microcapsules, microspheres, liposomes and niosomes (also known as nonionic surfactant vesicles) and the like.
  • a particulate dispersion system including polymeric micelles, nanoemulsions, submicroemulsions, microcapsules, microspheres, liposomes and niosomes (also known as nonionic surfactant vesicles) and the like.
  • the compounds of the present invention are synthesized using the methods described herein or other methods well known in the art.
  • Thin layer chromatography was carried out on a silica gel GF254 precoated plate (Qingdao Marine Chemical Plant). Column chromatography was carried out by silica gel (300-400 mesh, Yantai Zhihuangwu Silica Gel Development Reagent Factory) under medium pressure or by a pre-packed silica gel cartridge (ISCO or Welch) with the use of an ISCO Combiflash Rf200 rapid purification system. The ingredient was developed by UV light ( ⁇ : 254 nm) or iodine vapor.
  • the compound was prepared by preparative HPLC and purified by a Waters Symmetry C18 (19 ⁇ 50 mm, 5 ⁇ m) column or a Waters X Terra RP 18 (30 ⁇ 150 mm, 5 ⁇ m) column, wherein a Waters preparative HPLC 600 equipped with a 996 Waters PDA detector and Micromass mod. ZMD single quadrupole mass spectrometry (electrospray ionization, cationic mode) were used.
  • Method 1 Phase A: 0.1% TFA/MeOH 95/5; Phase B: MeOH/H 2 O 95/5. Gradient: proceeding at 10 to 90% B for 8 min, keeping at 90% B for 2 min; flow rate 20 mL/min.
  • Method 2 Phase A: 0.05% NH 4 OH/MeOH 95/5; Phase B: MeOH/H 2 O 95/5. Gradient: proceeding at 10 to 100% B for 8 min, keeping at 100% B for 2 min. Flow rate 20 mL/min.
  • Electrospray (ESI) mass spectra were obtained via Finnigan LCQ ion trap.
  • HPLC-UV-MS analysis for evaluation of compound purity was performed by combining an ion trap MS device and an HPLC system SSP4000 (Thermo Separation Products) equipped with an autosampler LC Pal (CTC Analytics) and a UV6000LP diode array detector (UV detection 215-400 nm). Device control, data acquisition and processing were performed with Xcalibur 1.2 software (Finnigan). HPLC chromatography was carried out at room temperature and a flow rate of 1 mL/min using a Waters X Terra RP 18 column (4.6 ⁇ 50 mm; 3.5 ⁇ m).
  • Mobile phase A was ammonium acetate 5 mM buffer (pH 5.5 with acetic acid): acetonitrile 90:10
  • mobile phase B was ammonium acetate 5 mM buffer (pH 5.5 with acetic acid): acetonitrile 10:90; proceeding at a gradient of 0 to 100% B for 7 min and then keeping at 100% B for 2 min before rebalancing.
  • reaction system was concentrated and dried, to which was then added 1 mL of methanol, 0.5 mL of 7.0 N NH 3 solution in methanol, followed by reacting overnight.
  • the resulting product was concentrated, and separated with silica gel column chromatography (dichloromethane/ammonia in methanol to obtain compound I-a.
  • I-n-10 MS m/z 630 [M + H] + .
  • I-n-11 TFA Salt MS m/z 605 [M + H] + .
  • I-n-12 TFA Salt MS m/z 621 [M + H] + .
  • I-n-13 TFA Salt MS m/z 539 [M + H] + .
  • the activity of compounds against kinase RET is evaluated by their effect of inhibiting growth of cell lines stably transfected with kinase CCDC6-RET-BaF3, KIF5B-RET-BaF3, and wild-type BaF3 ( Proc. Natl. Acad. Sci. USA., 2006, 103, 3153-8.).
  • the growth of the cell lines stably transfected with kinase CCDC6-RET-BaF3, KIF5B-RET-BaF3 depends on their kinase activity.
  • a compound can inhibit the activity of the kinase RET per se or the activity of the RET signaling pathway, the compound can inhibit the growth of BaF3 cells stably transfected with kinase. While the growth of wild-type BaF3 cells does not depend on the activity of RET or RET signaling pathway, the effect of a compound on the growth of wild-type BaF3 cells can be used to evaluate its broad-spectrum toxicity. Therefore, a larger ratio between IC 50 of a compound to wild-type BaF3 and IC 50 of the compound to the cell lines stably transfected with kinase CCDC6-RET-BaF3, KIF5B-RET-BaF3 indicates better targeting.
  • DMEM Dulbecco's modified eagle medium
  • RPMI 1640 containing 10% fetal bovine serum, 100 ⁇ g/mL ampicillin, 100 ⁇ g/mL streptomycin
  • MTS reaction solution containing 2 mg/mL of MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner Salt]; 100 ⁇ g/mL PES (phenazine methosulfate)).
  • the cell plate with uniformly mixed compound was cultured in a cell culture incubator (37° C.; 5% CO 2 ) for 48 h, then 20 ⁇ L of MTS reaction solution was added, uniformly mixed and incubated in the cell culture incubator (37° C.; 5% CO 2 ) for 1-4 hr, OD values at 490 nm were measured by a microplate reader (VARIOSKAN FLASH, Thermo).
  • a microplate reader VARIOSKAN FLASH, Thermo
  • Three parallels were set in each group of experiments, with 0.1% (a final concentration) DMSO as a negative control, and a medium without cells or compounds as a blank control.
  • IC 50 calculation The semi-inhibitory concentration of the compound acting on cell growth was calculated using GradPad Prism 5 software according to the measured cell growth inhibition rate.
  • III-j-7 1268 1367 2564 III-j-8 1135 1315 1881 III-j-9 97.6 463.9 4258 III-j-10 233.6 427.8 1456 III-j-11 1529 1568 1365 III-j-12 2662 2973 2151 III-j-13 1715 2402 4153 III-j-14 876.3 1379 1344 III-j-15 744.6 619.9 1205 III-j-16 2039 1468 2277 III-j-18 477.1 1353 >10000 III-k-1 1862 1320 4155 III-k-2 0.79 17.2 1342 III-k-3 1248 1188 1167 III-k-4 11.2 70.7 1622 III-k-5 1488 1915 4365 III-k-6 989.7 1012 2474 III-k-7 2961 1900 3715 III-k-8 3458 3576 3990 III-k-9 1188 1489 1650 III-k-10 2297 2438 1439 III-k-11 451.1 495.9 1289 III-k-12 1813 2662 n.d.
  • III-k-13 1447 1547 1603 III-k-15 2201 2380 n.d. III-k-16 2087 3194 3631 III-k-17 1411 2615 2633 III-k-18 4125 3994 3887 III-l-2 22.68 5.705 n.d. III-l-3 1403 1544 n.d. III-l-4 18.67 11.31 n.d. III-m-1 4503 2102 n.d. III-m-2 3626 1306 n.d.
  • III-m-3 2706 2406 3100 III-m-4 2723 3863 3459 III-m-5 3758 4041 3919 III-m-6 3772 3948 2786 III-m-7 1412 2346 4328 III-m-8 1238 1712 4097 III-m-9 1254 3049 1444 III-m-10 543.9 1049 622.9 III-m-12 4021 4277 3576 III-m-13 3510 2995 3394 III-m-14 2919 2720 3192 III-m-15 2958 3931 7206 III-m-16 3672 4422 4362 III-m-17 3153 2761 n.d.
  • III-m-18 2965 2678 3511 III-m-19 2512 3273 4023 III-m-20 2961 2500 3554 III-m-21 3491 3747 2921 III-m-22 597.1 854.1 >10000 III-m-23 514.7 476.6 463.5 III-m-24 3122 3232 3080 III-m-26 1318 2898 4096 III-m-27 1401 1501 34462 III-n-2 53.72 21 n.d. III-n-4 43.12 17.18 n.d.
  • III-r-2 385.6 535.3 4134 III-r-3 3773 2721 3651 III-r-4 186.8 324.9 1378 III-v-1 431.3 834.5 >10000 III-v-2 ⁇ 4 35927 n.d. III-v-3 23766 21289 n.d. III-v-4 ⁇ 4 76095 n.d. III-v-5 ⁇ 4 304425 n.d. III-v-6 ⁇ 4 48058 n.d. III-v-7 147612 14159 n.d. III-v-8 10940 4339 n.d. III-v-9 4210 1750 n.d. III-v-10 ⁇ 4 34976 n.d. III-v-11 3334 1457 n.d.
  • VI-j-1 2695 3957 3383 VI-j-2 3.076 16.96 3942
  • VI-l-1 2643 3218 4621
  • VI-m-1 1236 1252 1583
  • VI-n-1 3244 2836 4191
  • VI-o-2 39.84 99.42
  • 1961 VI-q-1 3568 3427 4357
  • VI-q-2 1517 1470 1516
  • VII-j-2 95.61 189.4 n.d.
  • VII-l-1 1017 1351 n.d.
  • DMEM Dulbecco's modified eagle medium
  • RPMI 1640 containing 10% fetal bovine serum, 100 ⁇ g/mL ampicillin, 100 ⁇ g/mL streptomycin
  • MTS reaction solution containing 2 mg/mL of MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner Salt]; 100 ⁇ g/mL PES (phenazine methosulfate)).
  • LC-2/AD cells (2 ⁇ 10 4 cells/well) were incubated into a 96-well culture plate, the volume of cell culture fluid was 90 ⁇ L, and then 10 ⁇ L of the compound at each gradient concentration was added (the highest concentration was 10 ⁇ M, which was diluted stepwise by 1 ⁇ 3, and 8 concentration points were set in total; the system contained 0.1% DMSO (dimethyl sulfoxide)).
  • the cell plate with uniformly mixed compound was cultured in a cell culture incubator (37° C.; 5% CO 2 ) for 48 h, then 20 ⁇ L of MTS reaction solution was added, uniformly mixed and incubated in the cell culture incubator (37° C.; 5% CO 2 ) for 1-4 hr; OD values at 490 nm were measured by a microplate reader (VARIOSKAN FLASH, Thermo).
  • Three parallels were set in each group of experiments, with 0.1% (a final concentration) DMSO as a negative control, and a medium without cells or compounds as a blank control.
  • IC 50 calculation The semi-inhibitory concentration of the compound acting on cell growth was calculated using GradPad Prism 5 software according to the measured cell growth inhibition rate.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
US16/626,015 2017-06-30 2018-06-29 Substituted aryl ether compound, preparation method thereof, pharmaceutical composition and use thereof Active US11319322B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN201710523136.4A CN109180677A (zh) 2017-06-30 2017-06-30 取代芳基醚类化合物、其制备方法、药用组合物及其应用
CN201710523136.4 2017-06-30
PCT/CN2018/093544 WO2019001556A1 (zh) 2017-06-30 2018-06-29 取代芳基醚类化合物、其制备方法、药用组合物及其应用

Publications (2)

Publication Number Publication Date
US20200123162A1 US20200123162A1 (en) 2020-04-23
US11319322B2 true US11319322B2 (en) 2022-05-03

Family

ID=64741137

Family Applications (1)

Application Number Title Priority Date Filing Date
US16/626,015 Active US11319322B2 (en) 2017-06-30 2018-06-29 Substituted aryl ether compound, preparation method thereof, pharmaceutical composition and use thereof

Country Status (5)

Country Link
US (1) US11319322B2 (zh)
EP (1) EP3647313A4 (zh)
JP (2) JP2020525409A (zh)
CN (2) CN109180677A (zh)
WO (1) WO2019001556A1 (zh)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SG11201803653QA (en) 2015-11-02 2018-05-30 Blueprint Medicines Corp Inhibitors of ret
CN109384782A (zh) * 2017-08-04 2019-02-26 厦门大学 取代五元并六元杂环类化合物、其制备方法、药物组合及其用途
CA3096043A1 (en) 2018-04-03 2019-10-10 Blueprint Medicines Corporation Ret inhibitor for use in treating cancer having a ret alteration
EP3833372A4 (en) 2018-08-10 2022-06-08 Blueprint Medicines Corporation TREATMENT OF EGFR MUTANT CANCER
CN111961034A (zh) * 2019-05-20 2020-11-20 浙江同源康医药股份有限公司 用作ret激酶抑制剂的化合物及其应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007004749A1 (en) 2005-07-05 2007-01-11 Takeda Pharmaceutical Company Limited Fused heterocyclic derivatives and use thereof
WO2011090738A2 (en) 2009-12-29 2011-07-28 Dana-Farber Cancer Institute, Inc. Type ii raf kinase inhibitors
CN103570723A (zh) * 2012-07-27 2014-02-12 四川大学 吡唑并嘧啶衍生物及其制备方法和在药物制备中的用途
WO2015089479A1 (en) 2013-12-13 2015-06-18 Dana-Farber Cancer Institute, Inc. Methods to treat lymphoplasmacytic lymphoma
WO2016130920A2 (en) 2015-02-13 2016-08-18 Dana-Farber Cancer Institute, Inc. Lrrk2 inhibitors and methods of making and using the same

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007004749A1 (en) 2005-07-05 2007-01-11 Takeda Pharmaceutical Company Limited Fused heterocyclic derivatives and use thereof
WO2011090738A2 (en) 2009-12-29 2011-07-28 Dana-Farber Cancer Institute, Inc. Type ii raf kinase inhibitors
CN103570723A (zh) * 2012-07-27 2014-02-12 四川大学 吡唑并嘧啶衍生物及其制备方法和在药物制备中的用途
US20150315191A1 (en) 2012-07-27 2015-11-05 Guangxi Wuzhou Pharmaceuticals (Group) Co., Ltd. 4-Position Substituted Pyrazolopyrimidine Derivative, And Use Thereof In Drug Preparation
WO2015089479A1 (en) 2013-12-13 2015-06-18 Dana-Farber Cancer Institute, Inc. Methods to treat lymphoplasmacytic lymphoma
WO2016130920A2 (en) 2015-02-13 2016-08-18 Dana-Farber Cancer Institute, Inc. Lrrk2 inhibitors and methods of making and using the same

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
International Preliminary Report on Patentability for Application No. PCT/CN2018/093544, dated Jan. 9, 2020.
International Search Report and Written Opinion dated Aug. 8, 2018, in connection with PCT/CN2018/093544.
J'nal of Het. Chem., 46, 459 (2009) J'nal of Med. Chem., 2015 58, 7431-7448. *
J'nal of Med. Chem. 2015, 58, 183-196 J'nal of Med. Chem 2013, 56, 1641-1655. *
Lawhorn et al., Identification of Purines and 7-Deazapurines as Potent and Selective Type I Inhibitors of Troponin I-Interacting Kinase (TNNI3K). J Med Chem. Sep. 24, 2015;58(18):7431-48. doi: 10.1021/acs.jmedchem.5b00931. Epub Sep. 10, 2015.
PCT/CN2018/093544, Aug. 8, 2018, International Search Report and Written Opinion.
PCT/CN2018/093544, Jan. 9, 2020, International Preliminary Report on Patentability.
Perspicace et al., Unexpected C—O Bond Formation in Suzuki Coupling of 4-Chlorothieno[2-3-d]pyrimidines. J. Heterocyclic. Chem., May 2009;46:459-64. doi: 10.1002/jhet.107.
Pinedo et al. (2000) McMahon et al. (2000). *
Tan et al., Discovery of type II inhibitors of TGFβ-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2). J Med Chem. Jan. 8, 2015;58(1):183-96. doi: 10.1021/jm500480k. Epub Jul. 30, 2014.
Vippagunta et al. (2001). *
Wang et al., Development of an UPLC-MS/MS method for quantification of Avitinib (AC0010) and its five metabolites in human cerebrospinal fluid: Application to a study of the blood-brain barrier penetration rate of non-small cell lung cancer patients. J Pharm Biomed Anal. May 30, 2017;139:205-214. doi: 10.1016/j.jpba.2017.02.057. Epub Mar. 4, 2017.
Yang et al., Structure-activity relationship studies of pyrazolo[3,4-d]pyrimidine derivatives leading to the discovery of a novel multikinase inhibitor that potently inhibits FLT3 and VEGFR2 and evaluation of its activity against acute myeloid leukemia in vitro and in vivo. J Med Chem. Feb. 28, 2013;56(4):1641-55. doi: 10.1021/jm301537p. Epub Feb. 19, 2013.

Also Published As

Publication number Publication date
EP3647313A4 (en) 2021-02-17
CN109180677A (zh) 2019-01-11
JP2020525409A (ja) 2020-08-27
WO2019001556A1 (zh) 2019-01-03
US20200123162A1 (en) 2020-04-23
JP2021165270A (ja) 2021-10-14
JP7439018B2 (ja) 2024-02-27
CN110770234B (zh) 2022-11-29
CN110770234A (zh) 2020-02-07
EP3647313A1 (en) 2020-05-06

Similar Documents

Publication Publication Date Title
US11319322B2 (en) Substituted aryl ether compound, preparation method thereof, pharmaceutical composition and use thereof
US11352354B2 (en) Substituted penta-fused hexa-heterocyclic compounds, preparation method therefor, drug combination and use thereof
US20220096450A1 (en) Compounds and Methods for Treating or Preventing Heart Failure
US11292787B2 (en) Five-membered-fused-six-membered aza-aromatic ring compound, preparation method thereof, pharmaceutical composition and application thereof
US8461179B1 (en) Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
US9024021B2 (en) Diarylacetylene hydrazide containing tyrosine kinase inhibitors
US11242317B2 (en) EBNA1 inhibitors and their method of use
TW200924778A (en) Amide compound
US10980809B2 (en) Urea-substituted aromatic ring-linked dioxane-quinazoline and -linked dioxane-quinoline compounds, preparation method therefor and use thereof
KR102429355B1 (ko) 티에노피리미딘 화합물, 그의 제조 방법, 약학 조성물 및 용도
US8912181B2 (en) Bicyclic compound or salt thereof
WO2013185353A1 (en) Compound as wnt signaling inhibitor, composition, and use thereof
WO2012155806A1 (zh) 4-氨基喹唑啉衍生物及其应用
US10954232B2 (en) Pyrazole derivative as ALK5 inhibitor and uses thereof
US20170273961A1 (en) Novel iminonitrile derivatives
JPWO2003026661A1 (ja) インスリン分泌促進剤及び新規なピリミジン誘導体
US20110306621A1 (en) Acylguanidine derivatives
WO2018157730A1 (zh) 脲取代的芳环连二噁烷并喹唑啉与连二噁烷并喹啉类化合物及其制备方法与应用
US20230399337A1 (en) Novel kinase inhibitors exhibiting anti-cancer activity and their method of use
US20200325156A1 (en) Heteroaryl amide compounds, preparation method therefor, pharmaceutical compositions thereof, and applications thereof
US9902709B2 (en) Polysubstituted pyridine compound, preparation method, use and pharmaceutical composition
US20200338084A1 (en) Inhibitors of low molecular weight protein tyrosine phosphatase (lmptp) and uses thereof
US20040176365A1 (en) Pde IV inhibitors

Legal Events

Date Code Title Description
FEPP Fee payment procedure

Free format text: ENTITY STATUS SET TO UNDISCOUNTED (ORIGINAL EVENT CODE: BIG.); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

AS Assignment

Owner name: XIAMEN UNIVERSITY, CHINA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:DENG, XIANMING;ZHANG, TING;KANG, QIAOFENG;AND OTHERS;REEL/FRAME:051390/0819

Effective date: 20191220

FEPP Fee payment procedure

Free format text: ENTITY STATUS SET TO SMALL (ORIGINAL EVENT CODE: SMAL); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

STPP Information on status: patent application and granting procedure in general

Free format text: APPLICATION DISPATCHED FROM PREEXAM, NOT YET DOCKETED

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER

STPP Information on status: patent application and granting procedure in general

Free format text: EX PARTE QUAYLE ACTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: NOTICE OF ALLOWANCE MAILED -- APPLICATION RECEIVED IN OFFICE OF PUBLICATIONS

STPP Information on status: patent application and granting procedure in general

Free format text: PUBLICATIONS -- ISSUE FEE PAYMENT VERIFIED

STCF Information on status: patent grant

Free format text: PATENTED CASE

CC Certificate of correction